Table 1. Fatty acid targeting drug development.
Summary of drugs developed to target fatty acid oxidation, fatty acid synthesis, and fatty acid uptake.
| Mechanism of Action | Target | Inhibitor | Selected Reference | Target Disease or Condition | Clinical trials (https://clinicaltrials.gov) |
|---|---|---|---|---|---|
| Fatty acid oxidation | |||||
| Inhibition of fatty acid β-oxidation and activation of pyruvate dehydrogenase | ACC | Ranolazine | Zacharowski et al., 2001; Samudio et al., 2010 | Chronic angina (FDA approval); acute myocardial infarction; leukemia | FDA approved (NDA #021526) |
| ACC (acetyl-CoA carboxylase) inhibitor, a PPAR-α agonist | ACC, PPARα | TOFA (5-(tetradecyloxy)-2-furoic acid) | Ottemann Abbamonte et al., 2021; Pizer et al., 2000; Guo et al., 2009 | Cutaneous lupus; systemic lupus erythematosus, glioblastoma; breast cancer | Phase 2 clinical trials (NCT03288324) |
| FAO activator | AMPK | A-769662 | Kemmerer et al., 2015; Goransson et al., 2007 | Type 2 diabetes (T2D); macrophages | NA |
| Inhibition of long-chain fatty acid import into mitochondria | CPT1 | Etomoxir | German et al., 2016; Pike et al., 2011 | Leukemia; glioblastoma | NA |
| Blocking FAO | Long-chain 3-ketoacyl-CoA thiolase (LCTH) | Trimetazidine | Gatta et al., 2017 | Precapillary pulmonary hypertension; muscle wasting (cachexia) | Phase 2 clinical trials (NCT03273387) |
| Fatty acid synthesis | |||||
| Fatty acid elongation | ACC | Soraphen-A | Beckers et al., 2007 | Prostate cancer; high fat diet-induced insulin resistance; hepatic steatosis | NA |
| Block lipigenesis | ACC | Firsocostat (GS-0976, NDI-010976, ND-630 | Alkhouri et al., 2020 | Non-alcoholic Steatohepatitis (NASH) | Phase 1 clinical trials (NCT02891408) |
| Inhibit TAG accumulation into lipid droplets | Acyl-CoA synthetases (ACS) | Triacscin C | Mashima et al., 2005 | Lung cancer; colon cancer; stomach cancer; brain cancer; and breast cancer | NA |
| FAS inhibitor | Acylglycerolphosphate acyltransferase (AGPAT) | CT-32501 | Takeuchi and Reue, 2009 | Prostate cancer | NA |
| ACLY inhibitor and AMPK activator in liver | ATP-citrate lyase (ACLY) and AMPK | ETC-1002 | Chen et al., 2020 | Hyperlipidemia | Phase 2 clinical trials (NCT02659397) |
| FAS activator | AMPK | Metformin | Bhansali et al., 2020 | Type 2 diabetes; solid cancer | FDA approved, Phase 4 clinical trials |
| FAS activator | AMPK | Aminoimidazole Carboxamide Riboside (AICAR) | Jose et al., 2011; Swinnen et al., 2005 | Lesch-Nyhan Syndrome; cancer | Phase 2 clinical trials (NCT00004314) |
| Blocking generation of acetyl-CoA for cholesterol and de novo fatty acid synthesis | ATP citrate lyase (ACLY) | SB-204990 | Hatzivassili ou et al., 2005; Ros et al., 2012 | Non-small cell lung cancer; solid cancer | NA |
| Blocking phosphatidylcholine (PC) biosynthesis | Choline kinase alpha (CKα) | TCD-717 | Glunde et al., 2011 | Solid cancer | Phase 1 clinical trials (NCT01215864) |
| Blocking fatty acid synthase and glutamate dehydrogenase activity | DNA methyltransferase, EGF receptors, HER-2 receptors, FASN | Epigallocatechin-3-gallate (EGCG) | Humbert et al., 2021 | Lung neoplasms; esophagitis | Phase 2 clinical trials (NCT02577393) |
| Blocking triglyceride (TG) synthesis | Diacylglycerol acyltransferase 1 (DGAT1) | A922500 | Zhao et al., 2008 | Obesity; dyslipidemia | NA |
| Suppressing triacylglyceride (TAG) plasma excursion and adipose tissue TAG synthesis | DGAT | AZD3988 | McCoull et al., 2012 | Type 2 diabetes (T2D); obesity | NA |
| Blocking TG synthesis | DGAT | AZD7687 | Morentin et al., 2019 | Obesity; overweight | Phase 1 clinical trials (NCT01119352) |
| Blocking TG synthesis | DGAT | JNJ DGAT2-A | Irshad et al., 2016 | Type 2 diabetes (T2D); solid cancer | NA |
| Blocking hydrolysis of triglycerides and the absorption of FFA | FASN | Orlistat | Schcolnik-Cabrera et al, 2018; Zhi et al., 1995 | Obesity; overweight | FDA approved |
| FASN antagonistic drug | FASN | TVB-2640 | Lolkema et al., 2015 | Non-alcoholic fatty liver disease | Phase 2 clinical trials (NCT049064210) |
| FAS inhibitor | Fatty acid synthase (FASN) and HMG-CoA reductase (HMGR) | Cerulenin | Currie et al., 2013; Lupu and Menendez, 2006; Ros et al., 2012 | Hepatic steatosis; solid cancer | NA |
| FAS inhibitor | Mitochondrial citrate transporter (CIC) | Benzene-tricarboxylate analog (BTA) | Catalina-Rodriguez et al., 2012 | Solid cancer | NA |
| Fatty acid amide hydrolase inhibitor | Monoacylglycerol lipase (MAGL) | JZL184 | Walenna et al., 2020; Taïb et al., 2019 | Type 2 diabetes (T2D); glioblastoma | NA |
| Blocking biosynthesis of monounsaturated fatty acids | Stearoyl-coA desaturase (SCD) | A939572 | von Roemeling et al., 2013 | Renal cell carcinoma | NA |
| Alters membrane fatty acid composition | SCD | BZ36 | Fritz et al., 2010 | Prostate cancer | NA |
| Blocking the conversion of saturated, long-chain fatty acyl-CoAs to monounsaturated | SCD | CAY10566 | Liu et al., 2007 | Breast cancer; lung cancer; colorectal cancer | NA |
| FAS inhibitor in liver | SCD | MK-8245 | Oballa et al., 2011 | Type 2 diabetes (T2D) | Phase 1 clinical trials (NCT00790556) |
| Inhibits the ER-Golgi translocation of SREBPs | SREBP1/2 | Fatostatin | Williams et al., 2013 | Prostate cancer | NA |
| Blocks biosynthesis and accumulation of fat | SREBP1/2 | FGH10019 | Williams et al., 2013, Kamisuki et al., 2011 | Prostate cancer | NA |
| Blocking SREBP activity | PI3Kα/β/δ | LY294002 | Migita et al., 2008 | Neuroblastoma; solid cancer | Phase 1 clinical trials |
| PPAR agonists drug for T2DM | PPARδ | Thiazolidinediones (TZDs) | Kim et al., 2001 | Type 2 diabetes (T2D) | FDA approved |
| Fat uptake | |||||
| Peptide mimetics of thrombospondin-1 (TSP-1) | CD36 | ABT-510 | Markovic et al., 2007 | Melanoma, renal cell carcinoma, lymphoma | Phase 2 clinical trials (NCT00602199) |